Transition metal catalyst complexes play important roles in many areas of chemistry, including the preparation of polymers and pharmaceuticals. The properties of the catalyst complexes are influenced by both the characteristics of the metal, and those of the ligands associated with the metal atom. For example, structural features of the ligands can influence reaction rate, regioselectivity, and stereoselectivity. Bulky ligands can be expected to slow reaction rate; electron-withdrawing ligands, in coupling reactions, can be expected to slow oxidative addition to, and speed reductive elimination from, the metal center; and electron-rich ligands, in coupling reactions, conversely, can be expected to speed oxidative addition to, and slow reductive elimination from, the metal center.
In many cases, the oxidative addition step in the accepted mechanism of a coupling reaction is deemed to be rate limiting. Therefore, adjustments to the catalytic system as a whole that increase the rate of the oxidative addition step should increase overall reaction rate. Additionally, all other factors being equal, the rate of oxidative addition of a transition metal catalyst to the carbon-halogen bond of an aryl halide is known to decrease as the halide is varied from iodide to bromide to chloride. Because of this fact, the more stable, lower molecular weight, and arguably more easy to obtain, members of the set of reactive organic halides—the chlorides—are typically the poorest substrates for traditional transition metal catalyzed coupling reactions and the like. Bromides have often been acceptable substrates, but have often required higher temperatures, longer reaction times, and have given lower yields of products.
Metal-catalyzed cross-coupling methodology to form carbon-carbon bonds has advanced organic synthesis. A., de Meijere, F. Diederich, Eds. Metal-Catalyzed Cross-Coupling Reactions, Vol. 2: Wiley-VCH, Weinheim, 2004. The Suzuki-Miyaura coupling is one of the preeminent methods for formation of carbon-carbon bonds and has been used in numerous synthetic ventures. N., Miyaura, Topics in Current Chem. 2002, 219, 11; and A. Suzuki, Organomet. Chem. 1999, 576, 147. A catalyst system that manifested high activity paired with extremely broad scope was recently reported. T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J. Am. Chem. Soc. 2005, 127, 4685; T. E. Barder, S. L. Buchwald Org. Lett. 2004, 6, 2649; S. D. Walker, T. E. Barder, J. R. Martinelli, S. L. Buchwald Angew. Chem. 2004, 116, 1907; and S. D. Walker, T. E. Barder, J. R. Martinelli, S. L. Angew. Chem. Int. Ed. 2004, 43, 1871. In addition, a catalyst system which provided excellent reactivity in the copper-free Sonogashira coupling of aryl chlorides/tosylates and terminal alkynes has been disclosed. D. Gelman, S. L. Buchwald Angew. Chem. 2003, 115, 6175; and D. Gelman, S. L. Buchwald Angew. Chem. Int. Ed. 2003, 42, 5993. However, this catalyst system was successful in coupling aryl alkynes only when the alkyne was added slowly over the course of the reaction. This fact is presumably due to competing non-productive oligomerization of the alkyne at higher concentrations in the presence of the catalyst. Further, a catalyst system and reaction conditions for the coupling of water-soluble aryl chlorides, and for the combination of difficult coupling partners in aqueous conditions, has been disclosed. Buchwald, S. et al., U.S. patent application Ser. No. 11/328,426, filed Jan. 9, 2006, hereby incorporated by reference in its entity.
Palladium-catalyzed C—N cross-coupling reactions are an important technology both in industry and academia. Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599; Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling Reactions (Eds.: de Meijere, A.; Diederich, F.), 2nd ed., Wiley-VCH, Weinheim, 2004; Hartwig, J. F. Synlett 2006, 1283. In recent years, the palladium-catalyzed coupling of amines with aryl halides or sulfonates has been investigated. Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131; Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125; Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2047. Unfortunately, these methods are still subject to undesirable limitations, notwithstanding the improvements in the substrate scope of palladium-catalyzed C—N bond-forming reactions realized by using weak bases, such as potassium phosphate or cesium carbonate. Old, D. W. et al. J. Am. Chem. Soc. 1998, 120, 9722; Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359. Although the use of weak bases allows for the use of substrates containing ester, cyano, nitro and keto groups in the reaction, reactions of aryl substrates containing alcohol, phenol, or amide functional groups remain problematic. But see Harris, M. H. et al. Org. Lett. 2002, 4, 2885. Despite these considerable advances in the field, notable limitations remain for which improved methods will have an immediate impact on the chemistry community. Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101; Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem. Int. Ed. 2005, 44, 1371; Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees, A.; Dingerdissen, U.; Beller, M. Chem. Eur. J. 2004, 10, 2983.
Also of importance is the monoarylation of primary amines via a cross-coupling reaction. Although this transformation has long been proficient with aryl bromides, recent progress has extended the method to aryl chlorides. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144; Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586; Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem. Int. Ed. 2005, 44, 1371. However, despite this success, challenges still remain, including the monoarylation of methylamine, which has yet to be described. Because it is the smallest aliphatic primary amine and therefore most likely to undergo diarylation, methylamine is a particularly challenging coupling partner to monoarylate.
Due to their high stability, good atom economy, and low cost, aryl mesylates represent an important substrate class for C—N cross-coupling reactions. Until recently, no procedure has been published for the amination of these materials. Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. J. Org. Chem. 2004, 69, 3447; Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 2754; So, M. C.; Zhou, Z.; Lau, C.; Kwong, F. Angew. Chem. Int. Ed. 2008, 47, Early View. However, amination reactions of aryl tosylates, benzenesulfonates, and nonaflates are known. Anderson, K. W.; Mendez-Perez, M.; Priego, J.; Buchwald, S. L. J. Org. Chem. 2003, 68, 9563; Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704; Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. Recently, it was demonstrated that substitution of the phosphine-containing arene in biarylmonophosphine ligands can have profound effects of the observed reactivity in catalytic reactions. Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald S. L. J. Am. Chem. Soc. 2007, 129, 13001.
However, there remains a need to develop improved ligands and reaction conditions (e.g., lower catalyst loadings) for a variety of cross-coupling reactions.